The principal function of the thyroid gland is to produce the hormones thyroxine (tetraiodothyronine, T4) and tri-iodothyronine (T3), both of which play essential roles in regulating intermediary metabolism in virtually all tissues and in maturation of the nervous system, skeletal muscle and lungs in the developing fetus and the newborn (Werner and Ingbar, The Thyroid: A fundamental and clinical text (Braverman and Utiger, eds.) (1991) pp. 1-1362, Lippincott, Philadelphia; DeGroot, Endocrinology (DeGroot, ed.) (1995) Grune and Stratton, Orlando, Fla.). T3 and T4 are unique hormones in that both contain iodine as an essential constituent.
The hormone-producing thyroid follicular cells or thyrocytes display a highly specialized ability to transport iodide, the anionic form of iodine. This ability is an apparent cellular adaptation to sequester environmentally scarce iodine, thus ensuring adequate thyroid hormone production in most cases. Nevertheless, insufficient dietary supply of iodine is still prevalent among millions of people in many regions of the world, leading to endemic iodine deficiency disorders (IDD) often associated with lower-than-normal thyroid hormone production (Medeiros-Neto, et al., Thyroid Research, (Robbins and Braverman, eds.), (1976) p. 497, Excerpta Medica, Amsterdam).
Administering thyroidal compounds is a common way of treating thyroid disorders and can also increase metabolism, energy expenditure, and fat loss while promoting healthy weight and proportion of lean body mass to adipose tissue. A major disadvantage of thyroidal compounds such as T3,T4, and diiodothyronine is the atrophy they cause to the thyroid gland due to negative feedback. This results in the diminishing of their effectiveness over time as the body's endogenous production lowers. Compounds that increase T3 and T4 levels without causing thyroidal atrophy and compounds that can prevent or reverse thyroidal atrophy are desirable.
Estrogen is a steroid hormone that, while having important functions including the control of reproduction and the development of secondary sexual characteristics, also plays a predominant role in breast cancer growth and development. The use of estrogen for its positive effects can also detrimentally result in the stimulation of other tissues, such as those of the breast and uterus, and increase the risk of cancer at these sites.
The estrogen receptor (ER) is a member of a nuclear receptor superfamily consisting of orphan receptors and receptors for classic high-affinity ligands, such as steroid hormones, vitamin D, retinoids, and thyroid hormones. As a ligand inducible transcription factor, the estrogen receptor mediates the activity of endogenous estrogens in the development and function of the female reproductive system, the maintenance of bone mineral density, regulation of blood lipid profile, brain function, cardiovascular health and other physiologic processes. Endogenous estrogens include 17β-estradiol and estrones. ER has been found to have two isoforms, ER-α and ER-β.
Estrogen-Related Receptors (ERRs) are included in the nuclear receptor family and were the first orphan nuclear receptors found through a search for genes encoding proteins related to known nuclear receptors. While it was originally believed that the development and physiological roles of ERRs were quite distant from those of the classic ERs, it has recently been shown that in some cases ERRs can share target genes, coregulatory proteins, ligands, and sites of action with the ERs. See Riggs, L; Hartman, L, Selective Estrogen-Receptor Modulators—Mechanisms of Action and Application to Clinical Practice. New England Journal of Medicine 384:7, 2003. Like ER, ERRs are also implicated in breast cancer and other diseases. See Giguere, V, To ERR in the Estrogen Pathway. Trends in Endocrinology & Metabolism, 13:220, 2002.
Therapeutic agents that modulate endogenous levels of estrogens and thereby affect activation of the ER and ERRs are desirable to treat diseases that are estrogen sensitive, estrogen receptor dependent or estrogen receptor mediated. These diseases include cancer, obesity, stroke, hormonal disorders, lipid disorders, metabolic disorders, diabetes, osteoporosis, and heart disease.